1. Field of the Invention
The invention relates to a composition and method for treating pancreatic enzyme insufficiency, particularly lipid malabsorbtion associated with cystic fibrosis.
2. Description of Related Art
Various diseased states such as pancreatitis, pancreatectomy and cystic fibrosis yield a condition in which insufficient digestive enzymes, particularly pancreatic enzymes, are available for the digestive process. Since the early part of the 20th century, pancreatic enzyme supplements derived from animal sources have been available for oral administration to patients with pancreatic enzyme deficiencies.
Pancreatic enzymes are active under near neutral and slightly alkaline conditions and under normal digestive processes would enter the digestive process in the duodenum where the pH conditions are favorable. However, when exogenous pancreatic enzymes are administered by an oral route, a problem exists, because animal derived pancreatic enzymes are not stable in the acid conditions of the stomach (pH 2.5 to 4), and a considerable portion of the exogenously administered pancreatic enzyme (if not all) is irreversibly inactivated.
Two approaches have been proposed for addressing this problem. Sipos has proposed encoating a pancreatic enzyme preparation in gastric acid resistant microspheres. (See U.S. Pat. Nos. 5,260,074; 5,324,514; 5,352,460; 5,405,621, for example, for detailed discussions of pancreatic enzyme preparations encapsulated in acid resistant microspheres and methods of making such preparations.)
Such compositions may be resistant to gastric juices but may be less than satisfactory for at least two reasons. First, studies by Graham (New England Journal of Medicine 296: pp. 1134-1317, Jun. 9, 1977) show that enteric-coated tablets were substantially less effective in steatorrhea reduction than uncoated tablets or capsules. Secondly, although the enteric coating has the theoretical advantage of allowing the enzyme preparation to pass through the hostile environment of the stomach to the small intestine where alkaline conditions should be more favorable to the pancreatic enzymes, the latter condition may not be met in patients with pancreatic insufficiency because the upper regions of the small intestine, e.g. the duodenum and upper jejunum are often acidic. Accordingly, the enzymes may not be released as anticipated and/or may still be inactivated by acidic conditions.
A second approach, suggested in U.S. Patent Applications 2001/0046493 and 2003/0017144, is the use of cross-linked lipase crystals in preparations for the treatment of pancreatic insufficiency. Cross-linking is believed to enhance the lipase's resistance to low pH. However, preparing cross-linked lipase involves significant preparation steps to prepare the cross-linked material, increasing the cost and difficulty of preparing the therapeutic agent.
Traditionally enzymes from animal sources have been used as exogenous sources for preparation of enzyme compositions for treatment of pancreatic insufficiency; animal derived pancreatic enzymes need bile acids or salts for proper activation. In diseases like cystic fibrosis, the secretion and/or availability of bile acids or salts is impeded by the mucus build up associated with the diseased state. Some pancreatic enzyme preparations include bile salts in addition to animal derived pancreatic enzymes. See, for example, U.S. Pat. No. 5,750,104.
In yet another approach, Galle, et al., in U.S. Patent Application 2004/0057944 discloses a microbial enzyme mixture as an alternative to animal enzymes for treating pancreatic insufficiency, including the insufficiency associated with cystic fibrosis. The composition of Galle, et al., includes a lipase from Rhizopus delemor, a protease from Aspergillus melleus and an amylase from Aspergillus oryzae, which have good pH stability and activity in the pH range of pH 4-8. The pH range in the stomach is typically pH 2.5-4. Hence, transit through the stomach exposes these enzymes to unfavorable conditions.
Accordingly, there remains a need for improved pancreatic enzyme preparations for treating pancreatic enzyme insufficiencies which can maintain their activity under the acid conditions of the stomach and perform their function in the small intestine with a high level of efficacy.